IL-17 is one kind of cytokine which was cloned from a T cell hybridoma of a mouse in 1993, and for which this protein was shown to have the NF-κB activating ability and the IL-6 inducing ability in 1995. IL-17 is a glycoprotein of a homodimer consisting of a peptide having a molecular weight of 20 to 30 kD, and it is currently known that it consists of six family molecules having homology (IL-17, IL-17B, IL-17C, IL-17D, IL-25(IL-17E), IL-17F) in addition to IL-17 (also referred to as IL-17A). It is known that IL-17 is produced mainly by an activated T cell (Th1 cell, Th2 cell), and acts on various cells such as fibroblast, epithelial cell, vascular endothelial cell, macrophage etc. to induce various factors such as inflammatory cytokine or chemokine, cell adhesion factor etc. to induce inflammation.
IL-17 is produced mainly from an activated T cell, while an IL-17 receptor (hereinafter, also referred to as IL-17R) is constitutively expressed in various cells. It is known that, like a ligand, a receptor forms a family (IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE).
Allergic airway inflammation such as bronchial asthma etc. is evoked by interaction between a hematopoietic cell which has infiltrated into an inflammatory location, such as Th2 cell, eosinophil, neutrophil, mast cell, basophil etc. and a tissue cell such as vascular endothelial cell, epithelial cell, fibroblast etc. The Th2 cell produces Th2 cytokine/chemokine such as IL-4, IL-5, IL-13, TARC/CCL17, MDC/CCL22 etc., and plays a central role in evoking allergic airway inflammation by inducement of IgE production, activation of eosinophil, production of a mucosal fluid and other cytokine/chemokine from airway epithelial cell, and expression of an adhesion molecule on vascular endothelial cell.
In recent years, as a new Th2 cell cytokine, IL-17E/IL-25 belonging to the IL-17 family has been identified (Non-Patent Literatures 1, 2). IL-17E/IL-25 is a ligand of IL-17RB, and it is thought that it has a role of inducing production of a Th2 cytokine such as IL-4, IL-5, IL-13 etc., and causing evocation or exacerbation of airway hypersensitivity and asthma (Non-Patent Literatures 5 to 7). However, details of a Th2 cytokine producing cell which becomes a target thereof, and particularly importance of a cell having a specified subset in involvement of IL-17E/IL-25 in allergic airway inflammation and airway hypersensitivity have not been revealed yet.
It is known that a natural killer T (NKT) cell recognizes glycosphingolipid as a ligand, which has been presented to an antigen presenting molecule CD1d on an antigen presenting cell (APC), is activated, and induces production of both Th1/2 cytokines and the cytotoxic activity to cause manifestation of the function particularly important in antitumor. Since the NKT cell has the aforementioned multifunction, it involves in remission of various morbids, while cases of involvement in exacerbation have been reported. It has been reported that an activation of the NKT cell particularly triggers pathogenesis and exacerbation of asthma (Non-Patent Literatures 3, 4). In addition, in therapy of asthma, symptomatic therapy using mainly an inhaled steroid is performed, but it is known that there are steroid non-sensitive asthma patients, and it has been reported that there is correlation with cases in which the NKT cell is involved in exacerbation, in many cases (Non-Patent Literature 4).
However, it has not been known that a specified subset of the NKT cell is important in involvement in asthma.
[Non-Patent Literature 1] Lee J., et al. IL-17E, a novel proinflammatoryligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem. 2001 Jan. 12; 276(2):1660-1664.
[Non-Patent Literature 2] Fort M. M., et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001 December; 15(6):985-995.
[Non-Patent Literature 3] Akbari O., et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med. 2003 May; 9(5):582-588.
[Non-Patent Literature 4] Umetsu D. T., DeKruyff R. H. A role for natural killer T cells in asthma. Nat Rev Immunol. 2006 December; 6(12):953-8.
[Non-Patent Literature 5] Angkasekwinai P., et al. Interleukin 25 promotes the initiation of proallergictype 2 responses. J Exp Med. 2007 Jul. 9; 204(7):1509-17.
[Non-Patent Literature 6] Wang Y. H., et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007 Aug. 6; 204(8):1837-47.
[Non-Patent Literature 7] Ballantyne S. J., et al. Blocking IL-25 prevents airway hyperresponsivenessin allergic asthma. J Allergy Clin Immunol. 2007 Sep. 20.